Dr. Eaton is a Board-Certified Veterinary Ophthalmologist and Assistant Clinical Professor of Ophthalmology at the University of Wisconsin-Madison. He received his veterinary degree with honors from the University of Pennsylvania and completed his residency in comparative ophthalmology at the University of California—Davis. He is also a clinical member of Ocular Services On Demand (OSOD) with experience in preclinical ocular drug development and toxicology and is a Comparative Ocular Consultant at EyeKor, Inc. with experience in preclinical study configuration and clinical trials for orphan retinal diseases. Prior to joining UW and OSOD/EyeKor, he established the ophthalmology service at Cornell University Veterinary Specialists (CUVS) in Stamford, Connecticut. His clinical and research interests include ocular pharmacology and toxicology, comparative retinal imaging, novel retinal therapeutics, and translational medicine and ophthalmology.
Seth Eaton
Recent Publications
2024
Comparative efficacy of low-volume retrobulbar anesthesia using three commercial local anesthetics in adult horses
J Am Vet Med Assoc. 2024 May 3:1-11. doi: 10.2460/javma.24.02.0121. Online ahead of print.
ABSTRACT
OBJECTIVE: To compare the efficacy of low-volume (5-mL) locoregional retrobulbar anesthesia ("retrobulbar block") by use of 3 commercial local anesthetic formulations.
ANIMALS: 8 healthy adult mares.
METHODS: A block-randomized, masked, controlled design was used. A single ultrasound-guided retrobulbar block was performed with 2% lidocaine, 2% mepivacaine, or 0.5% bupivacaine (n = 5 eyes/group). Contralateral eyes served as untreated controls. End points performed at baseline and time intervals up to 24 hours postblock included the following: assessment of neurophthalmic reflexes/responses, intraocular pressure, and vertical pupil diameter measurement, corneal and periocular esthesiometry, and observation for adverse effects.
RESULTS: Low-volume block did not result in increased intraocular pressure or other adverse effects at any time point in any treatment group. Statistically significant corneal anesthesia (P < .001) was observed 1 minute after block in all groups, persisting through 4 hours after lidocaine or mepivacaine block and through 24 hours after bupivacaine block. Clinically significant periocular anesthesia was not observed in any group. Significant vertical pupil diameter increase (P < .05) was observed for up to 4 hours after lidocaine or mepivacaine block and 6 hours after bupivacaine block.
CLINICAL RELEVANCE: Low-volume retrobulbar block with any of the 3 local anesthetic drugs evaluated was not associated with adverse effects. In terms of efficacy, mepivacaine block showed no clinical advantage over lidocaine block. However, bupivacaine block induced comparatively rapid and sustained corneal anesthesia. In comparison to published findings using a larger injection volume, low-volume retrobulbar block with lidocaine produced clinically comparable corneal anesthesia. However, periocular soft tissue anesthesia was not achieved with any local anesthetic drug at low volume.
PMID:38701834 | DOI:10.2460/javma.24.02.0121
2023
Evaluation for endotoxin in intraocular materials used during phacoemulsification surgery using a recombinant factor C assay
Vet Ophthalmol. 2023 Sep 22. doi: 10.1111/vop.13149. Online ahead of print.
ABSTRACT
OBJECTIVE: Cataract surgery remains the sole method to resolve blindness secondary to cataract formation. One complication includes fibrin web formation post-operatively. This study aimed to investigate the presence of endotoxin within materials used during cataract surgery as a possible cause of fibrin web phenomenon.
METHODS: Preservative-free epinephrine, heparin, viscoelastic devices, and intraocular lenses were collected for evaluation. Various manufacturers and manufacturing lot numbers were used when available. Viscosity of viscoelastics was reduced by incubating samples with human recombinant hyaluronidase. Intraocular product (IOL) packaging fluid was collected and stored for testing. The IOLs were then washed with a sterile balanced salt solution, incubated at 37°C for 48 h, and then fluid was collected for testing to mimic intraocular placement. Samples were tested using a commercially available rFC kit. Fluorescence was measured at time zero and after 1 h using a fluorescence microplate reader. The change in fluorescence was corrected for blank fluorescence and plotted to a standard curve.
RESULTS: Endotoxin levels were below the limit of detection (0.05 EU/mL) in all samples. Incubation of IOLs at intraocular temperature did not increase extraction of endotoxin.
CONCLUSION: Endotoxin was not identified in any tested sample, including those used in cases of fibrin web formation post-phacoemulsification. As fibrin webs are often observed episodically, it is possible that endotoxin levels may vary between batches, or that endotoxin is not related to fibrin formation.
PMID:37736864 | DOI:10.1111/vop.13149
2022
Retrospective investigation of perioperative risk factors for immediate postoperative corneal erosions in dogs undergoing phacoemulsification
Vet Ophthalmol. 2023 May;26(3):191-204. doi: 10.1111/vop.13040. Epub 2022 Nov 16.
ABSTRACT
OBJECTIVE: To characterize the incidence, contributing risk factors, and healing characteristics of immediate postoperative corneal erosions (IPCE) in dogs undergoing routine phacoemulsification.
ANIMALS STUDIED: Medical records of 313 canine eyes (159 dogs) undergoing routine phacoemulsification surgery.
PROCEDURES: Medical records of dogs undergoing planned cataract surgery at UW Veterinary Care were retrospectively reviewed. Patient-related variables including age, skull conformation, diabetes status, and cataract stage at the time of surgery were recorded. Intraoperative variables per eye were also recorded including surgical technique, surgeon expertise level, average phacoemulsification power, and phacoemulsification time. Diagnosis of IPCE ≤ 24 h after completion of surgery and time to IPCE healing were recorded where follow-up data were available.
RESULTS: Immediate postoperative corneal erosions were observed in 48/313 (15.3%) operated eyes. The presence of diabetes mellitus or brachycephalic skull conformation, preoperative Schirmer tear test (STT) value, surgical technique and surgeon experience level, phacoemulsification time, and absolute phacoemulsification time were not statistically significant risk factors for IPCE. Average phacoemulsification power was associated with IPCE (RR 1.52, p = .001). Time to IPCE healing was similar in diabetic and non-diabetic dogs (median [IQR] 8 [6-11] days and 8 [6-15] days, respectively). Diabetes mellitus, brachycephaly, and phacoemulsification parameters were not associated with IPCE healing at 7 or 14 days postoperatively.
CONCLUSIONS: Higher average phacoemulsification power may be associated with the development of IPCE in canine eyes. The presence of diabetes mellitus or brachycephaly are not risk factors for the development of IPCE, nor are they factors that influence IPCE healing.
PMID:36383040 | DOI:10.1111/vop.13040
2021
Retrobulbar lidocaine injection via the supraorbital fossa is safe in adult horses but produces regionally variable periocular anaesthesia
Equine Vet J. 2021 Aug 16. doi: 10.1111/evj.13496. Online ahead of print.
ABSTRACT
BACKGROUND: Injection techniques for retrobulbar anaesthesia are published in horses, but neither safety nor anaesthetic efficacy and duration have been evaluated objectively in vivo.
OBJECTIVE: To characterise the safety and efficacy of one published technique for retrobulbar anaesthesia.
STUDY DESIGN: Randomised, controlled descriptive experiment.
METHODS: Unilateral retrobulbar injection with 10 mL lidocaine (2%) was performed in eight sedated adult mares. Contralateral eyes served as untreated controls. Neurophthalmic parameters, intraocular pressure (IOP), and corneal and periocular sensation were measured awake, post-sedation and at periodic time points for 24 hours following injection. Adverse effects were documented.
RESULTS: Injection of 10 mL lidocaine significantly increased IOP for up to 2 hours (P < .05) maximally at 30 min (mean [95% CI]: 6.0 [2.7, 9.2] mm Hg, P < .001). Six of the eight treated eyes developed mild to moderate reversible chemosis for 2 to 24 hours. One eye developed severe chemosis and superficial corneal ulceration at 24 and 48 hours following injection respectively. Corneal sensitivity significantly decreased for 6 hours (P < .05), maximally at 10 min (-44.4 [-34.6, -54.1] mm, P < .001). Periocular sensitivity (measured as increase in applied force) significantly decreased dorsally and medially for up to 2 hours (maximal at 2 hours (367.1 [238.5, 495.7] g, P < .001, and at 30 min: 345.8 [202.6, 488.9] g, P < .001) respectively). Ventral and lateral sensitivity were not effectively decreased beyond 30 min. Optic nerve function was not consistently reduced following injection.
MAIN LIMITATIONS: Investigators were not masked to the treated eye.
CONCLUSIONS: Retrobulbar injection using 10 mL lidocaine is safe in normal eyes of adult horses, but carries risk in structurally compromised or glaucomatous eyes due to transient IOP increase. Reversible chemosis commonly develops 2-4h following injection, and may be severe in some horses with risk for corneal ulceration. Corneal anaesthesia is rapid and prolonged, but all periocular regions are not consistently anaesthetised. Retrobulbar injection should be combined with other local anaesthetic injections for eyelid surgeries or enucleations.
PMID:34396584 | DOI:10.1111/evj.13496
2019
Normative Values for Multifocal ERGs Recorded from Cynomolgus Macaques in a Non-clinical Setting
In Investigative Ophthalmology & Visual Science (Vol. 60, No. 9)
2017
Effects of topically applied heterologous serum on reepithelialization rate of superficial chronic corneal epithelial defects in dogs
J Am Vet Med Assoc. 2017 May 1;250(9):1014-1022. doi: 10.2460/javma.250.9.1014.
ABSTRACT
OBJECTIVE To assess the effects of topical application of undiluted heterologous serum on time to corneal reepithelialization in dogs with superficial chronic corneal epithelial defects (SCCEDs). DESIGN Multicenter, randomized, double-masked, controlled clinical trial. ANIMALS 41 client-owned dogs. PROCEDURES After collection of baseline clinical and historical data, dogs were randomly assigned to receive topically applied undiluted heterologous serum (n = 22) or isotonic saline (0.9% NaCl) solution (19) along with tobramycin and atropine. Epithelial debridement (at all visits) and grid keratotomy (at visits 2, 3, and 4) of SCCEDs were performed. Ophthalmic examination including fluorescein application was performed once weekly for 4 weeks or until corneal reepithelialization. Clinicians and owners were masked to treatment group. RESULTS No differences in baseline data were detected between treatment groups. No difficulties with medication administration, noncompliance, or adverse reactions were noted. All SCCEDs in both groups healed by 4 weeks after treatment began. Median time to reepithelialization (2 weeks) was not significantly different between serum-treated and placebo-treated eyes. Irrespective of treatment group, median time to reepithelialization was not significantly different for Boxers versus non-Boxer breeds. Direct correlations were detected between time to reepithelialization and vascularization score at study entry, vascularization score at time of reepithelialization, and ulcer area at study entry in both groups. Time to reepithelialization was not correlated with age, sex, or duration of signs in either group. CONCLUSIONS AND CLINICAL RELEVANCE Topical application of undiluted heterologous serum was well tolerated by dogs with SCCEDs but, as an adjunct to standard treatment, did not reduce time to corneal reepithelialization.
PMID:28414606 | DOI:10.2460/javma.250.9.1014
The SPOTS system: an ocular scoring system optimized for use in modern preclinical drug development and toxicology
Journal of Ocular Pharmacology and Therapeutics, 33(10), pp.718-734
2016
Species differences in the geometry of the anterior segment differentially affect anterior chamber cell scoring systems in laboratory animals
Journal of Ocular Pharmacology and Therapeutics 32(1), pp 28-37
Variability in the Electroretinographic Response of Laboratory Animals
Investigative Ophthalmology & Visual Science, 57(12), pp.5766-5766
2010
Equine protozoal myeloencephalitis due to Neospora hughesi and equine motor neuron disease in a mule
Vet Ophthalmol. 2010 Jul;13(4):259-65. doi: 10.1111/j.1463-5224.2010.00790.x.
ABSTRACT
CASE DESCRIPTION: A 23-year-old female mule was presented for bilateral ocular abnormalities and an abnormal pelvic limb gait.
CLINICAL FINDINGS: Anisocoria, unilateral enophthalmos, medial strabismus, ptosis, pupillary light reflex deficits, and bilateral reticulated pigmentary retinopathy were observed on ophthalmic examination. Neurologic abnormalities included right-sided facial nerve paralysis, extensive symmetric muscle atrophy, and asymmetric pelvic limb ataxia with an abnormal pelvic limb gait. A positive titer (1:40) for equine protozoal myeloencephalitis (EPM) associated with Neospora hughesi was obtained from cerebrospinal fluid with minimal (<1 red blood cell/microL) blood contamination. Muscle biopsies of the sacrocaudalis dorsalis medialis muscle revealed predominantly type I neurogenic muscle atrophy, consistent with a diagnosis of equine motor neuron disease (EMND).
TREATMENT AND OUTCOME: Treatment included a 2-month course of ponazuril (5 mg/kg PO q24 h), vitamin E (8000 IU PO q24 h), and selenium (2 mg PO q24 h). Clinical improvement was not observed after 2 months although the mule remained stable. Clinical deterioration was reported upon discontinuation of the ponazuril after a 2-month course.
CONCLUSION: Concurrent disease with EPM associated with N. hughesi and EMND should be considered in cases demonstrating cranial nerve abnormalities, pronounced symmetric muscle atrophy, unusual asymmetric gait abnormalities, and reticulated pigmentary retinopathy.
PMID:20618805 | DOI:10.1111/j.1463-5224.2010.00790.x
2009
Loss of p53 causes mitochondrial DNA depletion and altered mitochondrial reactive oxygen species homeostasis
Biochim Biophys Acta. 2009 May;1787(5):328-34. doi: 10.1016/j.bbabio.2009.01.004. Epub 2009 Jan 20.
ABSTRACT
In addition to its central role in cellular stress signaling, the tumor suppressor p53 modulates mitochondrial respiration through its nuclear transcription factor activity and localizes to mitochondria, where it enhances apoptosis and suppresses mitochondrial DNA (mtDNA) mutagenesis. Here we demonstrate a new conserved role for p53 in mtDNA copy number maintenance and mitochondrial reactive oxygen species (ROS) homeostasis. In mammals, mtDNA is present at thousands of copies per cell and is essential for normal development and cell function. We show that p53 null mouse and p53 knockdown human primary fibroblasts exhibit mtDNA depletion and decreased mitochondrial mass under normal culture growth conditions. This is accompanied by a reduction of the p53R2 subunit of ribonucleotide reductase mRNA and protein and of mitochondrial transcription factor A (mtTFA) at the protein level only. Finally, p53-depleted cells exhibit significant disruption of cellular ROS homeostasis, characterized by reduced mitochondrial and cellular superoxide levels and increased cellular hydrogen peroxide. Altogether, these results elucidate additional mitochondria-related functions for p53 and implicate mtDNA depletion and ROS alterations as potentially relevant to cellular transformation, cancer cell phenotypes, and the Warburg Effect.
PMID:19413947 | PMC:PMC2680458 | DOI:10.1016/j.bbabio.2009.01.004
2008
Anterior cervicoplasty: Neck rejuvenation using local anesthesia
J Am Acad Dermatol. 2008 Mar;58(3):430-3. doi: 10.1016/j.jaad.2007.12.003.
ABSTRACT
There is a subset of male patients that is troubled by redundant midline skin of the neck. Such patients may not be interested in having a face lift; they simply want elimination of the "turkey neck" appearance. Removal of redundant skin and underlying tissue can produce excellent results. We report our use of anterior cervicoplasty consisting of submental excision, midline platsymal placation and cutaneous Z-plasty using only minimal oral sedation and local anesthesia. This procedure can be a safe alternative to a face-lift for a select group of patients.
PMID:18280339 | DOI:10.1016/j.jaad.2007.12.003
A yeast model reveals biochemical severity associated with each of three variant alleles of galactose-1P uridylyltransferase segregating in a single family
J Inherit Metab Dis. 2008 Feb;31(1):97-107. doi: 10.1007/s10545-007-0786-5. Epub 2008 Jan 22.
ABSTRACT
Classic galactosaemia is a potentially lethal inborn error of metabolism that results from profound impairment of galactose-1P uridylyltransferase (GALT). Like many autosomal recessive disorders, classic galactosaemia demonstrates marked allelic heterogeneity; many if not most patients are compound heterozygotes. Owing in part to the fact that most GALT mutations are never observed in patients in the homozygous state, in part to concerns of possible allelic interaction, and in part to the broad range of GALT activity levels associated with the affected, carrier, and control states, definition of the specific functional consequence of individual variant GALT alleles from studies of clinical samples alone can be a challenging task. To overcome this problem we previously developed and applied a null-background yeast system to enable functional analyses of human GALT alleles expressed individually or in defined pairs. We report here the application of this system to characterize three distinct variant alleles of GALT identified within a single family. Of these alleles, one carried a missense mutation (K285N) that has previously been reported and characterized, one carried a nonsense mutation (R204X) that has previously been reported but not characterized, and the third carried a missense substitution (T268N) that was novel. Our studies reported here reconfirm the profound nature of the K285N mutation, demonstrate that the R204X mutation severely compromises both expression and function of human GALT, and finally implicate T268N as one of a very small number of naturally occurring rare but neutral missense polymorphisms in human GALT.
PMID:18210213 | DOI:10.1007/s10545-007-0786-5
2007
Distinct roles of galactose-1P in galactose-mediated growth arrest of yeast deficient in galactose-1P uridylyltransferase (GALT) and UDP-galactose 4'-epimerase (GALE)
Mol Genet Metab. 2008 Feb;93(2):160-71. doi: 10.1016/j.ymgme.2007.09.012. Epub 2007 Nov 5.
ABSTRACT
Galactose is metabolized in humans and other species by the three-enzyme Leloir pathway comprised of galactokinase (GALK), galactose 1-P uridylyltransferase (GALT), and UDP-galactose 4'-epimerase (GALE). Impairment of GALT or GALE in humans results in the potentially lethal disorder galactosemia, and loss of either enzyme in yeast results in galactose-dependent growth arrest of cultures despite the availability of an alternate carbon source. In contrast, loss of GALK in humans is not life-threatening, and in yeast has no impact on the growth of cultures challenged with galactose. Further, the growth of both GALT-null and GALE-null yeast challenged with galactose is rescued by loss of GALK, thereby implicating the GALK reaction product, gal-1P, for a role in the galactose-sensitivity of both strains. However, the nature of that relationship has remained unclear. Here we have developed and applied a doxycycline-repressible allele of galactokinase to define the quantitative relationship between galactokinase activity, gal-1P accumulation, and growth arrest of galactose-challenged GALT or GALE-deficient yeast. Our results demonstrate a clear threshold relationship between gal-1P accumulation and galactose-mediated growth arrest in both GALT-null and GALE-null yeast, however, the threshold for the two strains is distinct. Further, we tested the galactose-sensitivity of yeast double-null for GALT and GALE, and found that although loss of GALT barely changed accumulation of gal-1P, it significantly lowered the accumulation of UDP-gal, and also dramatically rescued growth of the GALE-null cells. Together, these data suggest that while gal-1P alone may account for the galactose-sensitivity of GALT-null cells, other factors, likely to include UDP-gal accumulation, must contribute to the galactose-sensitivity of GALE-null cells.
PMID:17981065 | PMC:PMC2253667 | DOI:10.1016/j.ymgme.2007.09.012
Ataxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis
J Clin Invest. 2007 Sep;117(9):2723-34. doi: 10.1172/JCI31604.
ABSTRACT
Ataxia-telangiectasia mutated (ATM) kinase orchestrates nuclear DNA damage responses but is proposed to be involved in other important and clinically relevant functions. Here, we provide evidence for what we believe are 2 novel and intertwined roles for ATM: the regulation of ribonucleotide reductase (RR), the rate-limiting enzyme in the de novo synthesis of deoxyribonucleoside triphosphates, and control of mitochondrial homeostasis. Ataxia-telangiectasia (A-T) patient fibroblasts, wild-type fibroblasts treated with the ATM inhibitor KU-55933, and cells in which RR is inhibited pharmacologically or by RNA interference (RNAi) each lead to mitochondrial DNA (mtDNA) depletion under normal growth conditions. Disruption of ATM signaling in primary A-T fibroblasts also leads to global dysregulation of the R1, R2, and p53R2 subunits of RR, abrogation of RR-dependent upregulation of mtDNA in response to ionizing radiation, high mitochondrial transcription factor A (mtTFA)/mtDNA ratios, and increased resistance to inhibitors of mitochondrial respiration and translation. Finally, there are reduced expression of the R1 subunit of RR and tissue-specific alterations of mtDNA copy number in ATM null mouse tissues, the latter being recapitulated in tissues from human A-T patients. Based on these results, we propose that disruption of RR and mitochondrial homeostasis contributes to the complex pathology of A-T and that RR genes are candidate disease loci in mtDNA-depletion syndromes.
PMID:17786248 | PMC:PMC1952633 | DOI:10.1172/JCI31604
Lymphangiosarcoma presenting as asymptomatic swelling of the cheek
J Am Acad Dermatol. 2007 Mar;56(3):530-1. doi: 10.1016/j.jaad.2006.09.036.
NO ABSTRACT
PMID:17317502 | DOI:10.1016/j.jaad.2006.09.036
2006
Excess ribonucleotide reductase R2 subunits coordinate the S phase checkpoint to facilitate DNA damage repair and recovery from replication stress
Biochem Pharmacol. 2007 Mar 15;73(6):760-72. doi: 10.1016/j.bcp.2006.11.014. Epub 2006 Nov 23.
ABSTRACT
Ribonucleotide reductase (RNR), which consists of R1 and R2 subunits, catalyzes a key step of deoxyribonucleoside triphosphate (dNTP) synthesis for DNA replication and repair. The R2 subunit is controlled in a cell cycle-specific manner for timely DNA synthesis and is negatively regulated by p53 in response to DNA damage. Herein we demonstrate that the presence of excess R2 subunits in p53(-/-) HCT-116 human colon cancer cells protects against DNA damage and replication stress. siRNA-mediated stable knockdown (>80%) of excess R2 subunits has no effect on proliferative growth but results in enhanced accumulation of gamma-H2Ax and delayed recovery from DNA lesions inflicted by exposure to cisplatin and Triapine. This accentuated induction of gamma-H2Ax in R2-knockdown cells is attributed to reduced ability to repair damaged DNA and overcome replication blockage. The lack of excess R2 subunits consequently augments chk1 activation and cdc25A degradation, causing impeded cell progression through the S phase and enhanced apoptosis in response to DNA damage and replication stress. In contrast, the level of R1 subunits appears to be limiting, since depletion of the R1 subunit directly activates the S phase checkpoint due to replication stress associated with impaired RNR activity. These findings suggest that excess R2 subunits facilitate DNA damage repair and recovery from replication stress through coordination with the S phase checkpoint in the absence of functional p53. Thus, the level of the R2 subunit constitutes an important determinant of the chemosensitivity of cancer cells and serves as a potential target for enhancement of DNA-damage based therapy.
PMID:17188250 | DOI:10.1016/j.bcp.2006.11.014
2005
Surgical pearl: thermoplastic bolster dressing for full-thickness skin grafts
J Am Acad Dermatol. 2006 Jan;54(1):152-3. doi: 10.1016/j.jaad.2005.06.029.
NO ABSTRACT
PMID:16384774 | DOI:10.1016/j.jaad.2005.06.029
Perineural spread of squamous cell carcinoma involving the spinal accessory nerve in an immunocompromised organ transplant recipient
Dermatol Surg. 2005 May;31(5):599-601. doi: 10.1111/j.1524-4725.2005.31173.
ABSTRACT
BACKGROUND: Squamous cell carcinoma is the second most common cutaneous malignancy in humans, affecting approximately 200,000 people in the United States each year. In immunocompromised patients, squamous cell carcinoma is the most common skin cancer, and it also tends to behave more aggressively than in immunocompetent patients.
OBJECTIVE: We describe an immunocompromised patient, previously treated for a squamous cell carcinoma of the left posterior shoulder, who subsequently developed a cord-like, intraneural metastasis of the spinal accessory nerve.
RESULTS: The patient presented with a 3-month history of lancinating pain of the left neck and shoulder. He had been treated previously for a squamous cell carcinoma of the left posterior shoulder, which subsequently recurred twice. On examination, a cord-like mass was palpable along the path of the spinal accessory nerve. Given the aggressive nature of this patient's squamous cell carcinoma, surgical exploration was performed. Frozen-section analysis of the spinal accessory nerve and of the multiple supraclavicular nerves revealed perineural and intraneural squamous cell carcinoma.
CONCLUSION: To our knowledge, this is the first reported case of a primary cutaneous squamous cell carcinoma of the trunk or extremity metastasizing to a cranial nerve.
PMID:15962752 | DOI:10.1111/j.1524-4725.2005.31173
Differential involvement of the related DNA helicases Pif1p and Rrm3p in mtDNA point mutagenesis and stability
Gene. 2005 Jul 18;354:86-92. doi: 10.1016/j.gene.2005.03.031.
ABSTRACT
With the exception of base excision repair, conserved pathways and mechanisms that maintain mitochondrial genome stability have remained largely undelineated. In the budding yeast, Saccharomyces cerevisiae, Pif1p is a unique DNA helicase that is localized both to the nucleus and mitochondria, where it is involved in maintaining DNA integrity. We previously elucidated a role for Pif1p in oxidative mtDNA damage resistance that appears to be distinct from its postulated function in mtDNA recombination. Strains lacking Pif1p (pif1Delta) exhibit an increased rate of formation of petite mutants (an indicator of mtDNA instability) and elevated mtDNA point mutagenesis. Here we show that deletion of the RRM3 gene, which encodes a DNA helicase closely related to Pif1p, significantly rescues the petite-induction phenotype of a pif1Delta strain. However, suppression of this phenotype was not accompanied by a corresponding decrease in mtDNA point mutagenesis. Instead, deletion of RRM3 alone resulted in an increase in mtDNA point mutagenesis that was synergistic with that caused by a pif1Delta mutation. In addition, we found that over-expression of RNR1, encoding a large subunit of ribonucleotide reductase (RNR), rescued the petite-induction phenotype of a pif1Delta mutation to a similar extent as deletion of RRM3. This, coupled to our finding that the Rad53p protein kinase is phosphorylated in the rrm3Delta pif1Delta double-mutant strain, leads us to conclude that one mechanism whereby deletion of RRM3 influences mtDNA stability is by modulating mitochondrial deoxynucleoside triphosphate pools. We propose that this is accomplished by signaling through the conserved Mec1/Rad53, S-phase checkpoint pathway to induce the expression and activity of RNR. Altogether, our results define a novel role for Rrm3p in mitochondrial function and indicate that Pif1p and Rrm3p influence a common process (or processes) involved in mtDNA replication, repair, or stability.
PMID:15907372 | DOI:10.1016/j.gene.2005.03.031
The conserved Mec1/Rad53 nuclear checkpoint pathway regulates mitochondrial DNA copy number in Saccharomyces cerevisiae
Mol Biol Cell. 2005 Jun;16(6):3010-8. doi: 10.1091/mbc.e05-01-0053. Epub 2005 Apr 13.
ABSTRACT
How mitochondrial DNA (mtDNA) copy number is determined and modulated according to cellular demands is largely unknown. Our previous investigations of the related DNA helicases Pif1p and Rrm3p uncovered a role for these factors and the conserved Mec1/Rad53 nuclear checkpoint pathway in mtDNA mutagenesis and stability in Saccharomyces cerevisiae. Here, we demonstrate another novel function of this pathway in the regulation of mtDNA copy number. Deletion of RRM3 or SML1, or overexpression of RNR1, which recapitulates Mec1/Rad53 pathway activation, resulted in an approximately twofold increase in mtDNA content relative to the corresponding wild-type yeast strains. In addition, deletion of RRM3 or SML1 fully rescued the approximately 50% depletion of mtDNA observed in a pif1 null strain. Furthermore, deletion of SML1 was shown to be epistatic to both a rad53 and an rrm3 null mutation, placing these three genes in the same genetic pathway of mtDNA copy number regulation. Finally, increased mtDNA copy number via the Mec1/Rad53 pathway could occur independently of Abf2p, an mtDNA-binding protein that, like its metazoan homologues, is implicated in mtDNA copy number control. Together, these results indicate that signaling through the Mec1/Rad53 pathway increases mtDNA copy number by altering deoxyribonucleoside triphosphate pools through the activity of ribonucleotide reductase. This comprises the first linkage of a conserved signaling pathway to the regulation of mitochondrial genome copy number and suggests that homologous pathways in humans may likewise regulate mtDNA content under physiological conditions.
PMID:15829566 | PMC:PMC1142443 | DOI:10.1091/mbc.e05-01-0053
2002
Regional anesthesia of the face
Dermatol Surg. 2001 Dec;27(12):1006-9. doi: 10.1046/j.1524-4725.2001.01853.x.
NO ABSTRACT
PMID:11849261 | DOI:10.1046/j.1524-4725.2001.01853.x
1994
A ten-year update of administrative relationships between state hospitals and academic psychiatry departments
Hosp Community Psychiatry. 1994 Nov;45(11):1113-6. doi: 10.1176/ps.45.11.1113.
ABSTRACT
OBJECTIVE: In a follow-up to a survey ten years earlier, the authors investigated current administrative relationships between academic departments of psychiatry and state hospitals.
METHODS: A 20-item questionnaire was sent to the chairs of the 110 medical school departments of psychiatry with accredited psychiatric residencies.
RESULTS: Eighty-two departments, or 75 percent, responded. Seventy-one percent of the respondents reported that their department had a relationship with a state hospital; 79 percent of these relationships involved the education of psychiatric residents. Most respondents rated the quality of the relationship favorably (4 or 5 on a 5-point scale). Almost all respondents believed that residents can obtain a high-quality education in a state hospital. More than half of the departments responding to a question about the importance of a state hospital rotation rated it of major importance in their residency program.
CONCLUSIONS: Many medical school departments of psychiatry remain closely involved with state hospitals and recognize the hospital as an important part of residents' education. Administrators have gained much experience about how to develop and implement mutually beneficial relationships.
PMID:7835859 | DOI:10.1176/ps.45.11.1113
Administrative relationships between community mental health centers and academic psychiatry departments: a 12-year update
Am J Psychiatry. 1994 May;151(5):722-7. doi: 10.1176/ajp.151.5.722.
ABSTRACT
OBJECTIVE: The authors investigated the administrative relationships in 1990 between medical school departments of psychiatry and community mental health centers (CMHCs).
METHOD: A 20-item questionnaire was sent to the chairpersons of the 110 medical school departments of psychiatry with accredited psychiatric residencies.
RESULTS: Sixty-nine percent of the chairpersons responded to the questionnaire. Sixty-eight percent of the responding chairpersons reported that their departments had relationships with CMHCs, and 90% of these relationships involved the education of psychiatric residents. Most responding chairpersons described the quality of their existing CMHC relationships as good to excellent. In the most common type of relationship reported the CMHC was used as a setting for resident education. The vast majority of responding chairpersons stated that quality resident education is possible in a CMHC, and about two-thirds of the responding chairpersons with CMHC relationships involving residency education rated the CMHC rotation as of major importance to their residency programs.
CONCLUSIONS: CMHCs continue to be an important and valued component of the educational experience for many psychiatric residents, and many departments of psychiatry have recognized the advantages and benefits of CMHCs for residency training. There are now considerable data on how a relationship between a medical school department and a CMHC should be structured to achieve maximum benefit for both the department and the CMHC.
PMID:8166314 | DOI:10.1176/ajp.151.5.722
1987
Financing of child psychiatry pediatric consultation-liaison programs
J Dev Behav Pediatr. 1987 Aug;8(4):221-8.
ABSTRACT
Child psychiatrists and pediatricians recognize the importance of providing psychosocial care for children and their families in medical settings. Consultation-liaison and behavioral pediatric programs provide most of the training in this area. Twenty-nine pediatric consultation-liaison program directors participated in an initial and follow-up telephone survey about their programs. In the 5 years between the surveys, there was a drastic reduction in federal funding for these programs. The findings include a change in the number and composition of both staff and trainees. There were major shifts in the financial support of the programs. The programs were involved in fewer activities and in more restricted settings at the time of the follow-up survey. Financing of pediatric consultation-liaison programs plays a major role in shaping the structure and function of the programs.
PMID:3611363
1986
Consultation-liaison psychiatry: unfinished business
Psychosomatics. 1986 May;27(5):323-4. doi: 10.1016/S0033-3182(86)72683-2.
NO ABSTRACT
PMID:3714949 | DOI:10.1016/S0033-3182(86)72683-2
1984
The VA psychiatry service as a setting for residency education
Am J Psychiatry. 1984 Aug;141(8):960-5. doi: 10.1176/ajp.141.8.960.
ABSTRACT
The authors report data from a survey of chairmen of academic departments of psychiatry and chiefs of Veterans Administration (VA) psychiatry services concerning administrative relationships between academic psychiatry departments and VA psychiatry services and the education of psychiatry residents in VA settings. The extent and quality of relationships, the interdependence of academic departments and VA psychiatry services, factors important for good VA training, and advantages and disadvantages of using the VA for residency education are documented. The authors present their conclusions and recommendations for improving the quality of relationships between academic departments and VA psychiatry services and for strengthening psychiatric education in the VA setting.
PMID:6465371 | DOI:10.1176/ajp.141.8.960
1983
Administrative relationships between state hospitals and academic psychiatry departments
Am J Psychiatry. 1983 Jul;140(7):898-901. doi: 10.1176/ajp.140.7.898.
ABSTRACT
To review administrative relationships between academic departments of psychiatry and state hospitals the authors sent a questionnaire survey to chairmen of the 115 psychiatry departments in the United States with approved residency programs, receiving responses from 98 (85%). They discuss three types of relationships and examine the nature of the training of university residents in state hospitals, providing suggestions for integrating service-oriented settings such as state hospitals into an academic psychiatry program.
PMID:6859309 | DOI:10.1176/ajp.140.7.898
1982
Medical students' evaluation of psychiatry: a cross-country comparison
Am J Psychiatry. 1982 Aug;139(8):1003-9. doi: 10.1176/ajp.139.8.1003.
ABSTRACT
The authors reviewed studies of attitudes toward psychiatry held by 368 medical students at the University of California, Los Angeles (UCLA), and 204 senior medical students from two schools in Washington, D.C. They found that the attitudes of all these students were remarkably similar: they viewed psychiatry as a worthwhile medical specialty but one of low prestige and low precision and thought that most psychiatric patients could be adequately managed by non-physicians. On the basis of their findings the authors offer recommendations for teaching basic psychiatric skills and for improving psychiatry's image and attractiveness.
PMID:7091421 | DOI:10.1176/ajp.139.8.1003
The CMHC as a setting for residency education
Community Ment Health J. 1982 Spring;18(1):3-10. doi: 10.1007/BF00757103.
ABSTRACT
The authors review four approaches chairmen of departments of psychiatry have used to attempt to ensure quality resident education in CMHCs they do not control. Several examples are presented of administrative problems that may develop in this type of relationship. Based on this material and the author's experience, a four stage administrative process is presented which emphasized clear identification of goals and objectives, negotiation of a relationship that is beneficial to both the development and the CMHC, development of a written contract, and careful monitoring and evaluation of its progress. Designing a relationship in this fashion offers maximum opportunity for programmatic success.
PMID:7083810 | DOI:10.1007/BF00757103
1981
Medical students' attitudes about psychiatry. Implications for psychiatric recruitment
Arch Gen Psychiatry. 1981 Oct;38(10):1144-54. doi: 10.1001/archpsyc.1981.01780350078009.
ABSTRACT
A questionnaire study of 204 senior medical students at two East Coast schools revealed that most were favorable about psychiatry and psychiatrists. When queried concerning criticisms, many stated doubts about the scientific rigor, therapeutic efficacy, and appropriate roles of psychiatrists. Psychiatric clerkships strongly influences student attitudes. Students were especially pleased with opportunities to work directly with patients and to observe psychiatrists doing so. Students were negatively influenced by the antipsychiatry views of nonpsychiatric faculty, house staff, and peers. The findings are discussed with reference to various explanations for the recent decline in psychiatric recruitment and a connection with the rise of family practice is proposed. Direct confrontation of student criticisms, questions, and misconceptions about psychiatry and advocacy of the special expertise and practice opportunities may improve both students' attitudes and psychiatric recruitment.
PMID:7294968 | DOI:10.1001/archpsyc.1981.01780350078009
1980
The biopsychosocial model in education: discussion
Psychosom Med. 1980;42(1 Suppl):131-3. doi: 10.1097/00006842-198001001-00006.
NO ABSTRACT
PMID:7413896 | DOI:10.1097/00006842-198001001-00006
1979
Psychiatry for the general physician: an educational imperative
Psychosomatics. 1979 Aug;20(8):552-6. doi: 10.1016/S0033-3182(79)70778-X.
NO ABSTRACT
PMID:493480 | DOI:10.1016/S0033-3182(79)70778-X
Administrative relationships between community mental health centers and academic psychiatry departments
Am J Psychiatry. 1979 Aug;136(8):1040-4. doi: 10.1176/ajp.136.8.1040.
ABSTRACT
The authors reviewed the administrative relationships between academic departments of psychiatry and community mental health centers (CMHCs). By telephone, they surveyed the chairpersons of 110 departments of psychiatry with approved psychiatric residency programs and found that 87 (79%) had some type of administrative relationship with a comprehensive CMHC. Almost two-thirds of the chairpersons of these departments considered the CMHC to be of major importance to their educational programs. Only 8 (7%) of the 110 departments had discontinued their relationship with a CMHC. Most of the chairpersons whose departments were involved with a center were optimistic about the future of their programs in CMHCs.
PMID:464128 | DOI:10.1176/ajp.136.8.1040
Updating comprehensive care
1978
Carbon flow in four lake ecosystems: a structural approach
Science. 1978 Dec 15;202(4373):1183-6. doi: 10.1126/science.202.4373.1183.
ABSTRACT
Direct and indirect carbon fluxes in lakes Marion (British Columbia), Findley (Washington), Wingra (Wisconsin), and Mirror (New Hampshire) are compared, using budgets and input-output analysis. Overall differences in carbon flow between the lakes are shown with cycling indices of .031, .108, .572, and .661, respectively. The results suggest that lake ecosystems may be considered unique aggregatins of similar components.
PMID:17735402 | DOI:10.1126/science.202.4373.1183
Academic psychiatry in the political marketplace
Arch Gen Psychiatry. 1978 Sep;35(9):1145-9. doi: 10.1001/archpsyc.1978.01770330119012.
ABSTRACT
There is pressure for all medicine to be publicly accountable and for there to be public manifestations of professional responsibility. The expectation of an immediate return on the public's investment in education is matched by cries for"relevence" in research. The generation and transmission of psychiatric knowledge is not compatible with such a direct telelogic approach. Yet, public accountability is necessary, considering the public monies involved. Academic psychiatry should become familiar with the political marketplace--a high-pressure environment where fiercely competing interests vie for the politician's attention through votes and contributions, and where the "squeaky wheel gets the grease". Psychiatry can ill afford to adopt a passive posture in this political marketplace. Psychiatrists bear responsibility for informing the public about the relevance of psychiatric research and education. The profession must accept--even embrace--the concept of public accountability as a synchronous extension of our professional responsibilities.
PMID:686975 | DOI:10.1001/archpsyc.1978.01770330119012
The evaluation of teaching and learning by psychiatric consultation and liaison training programs
Psychosom Med. 1978 Mar;40(2):99-106. doi: 10.1097/00006842-197803000-00002.
NO ABSTRACT
PMID:652921 | DOI:10.1097/00006842-197803000-00002
1977
Psychiatry in crisis
Am J Psychiatry. 1977 Jun;134(6):642-5. doi: 10.1176/ajp.134.6.642.
ABSTRACT
Psychiatry today faces sociopolitical, economic, and philosophical pressures that threaten its existence as a valued medical specialty. Recent legislation that decreases the numbers of foreign medical graduates eligible to practice in the United States, increases the numbers of community mental health centers and types of services they offer, and limits federal support of psychiatric education will affect the future of psychiatry as a profession and discipline. Forthcoming legislation and federal health policies will be related to the ability of the profession to demonstrate its unique role in the provision of mental health and health services. The authors offer suggestions for the education of the American public regarding the important role of psychiatry in America's health and mental health care system.
PMID:869029 | DOI:10.1176/ajp.134.6.642
The educational challenge of consultation-liaison psychiatry
Am J Psychiatry. 1977 Mar;134 Suppl:suppl 20-3.
ABSTRACT
The authors examine issues related to quality of psychiatric consultation-liaison education programs on the basis of data from the fiscal year 1975 NIMH review of grant proposals for 71 such programs. This category received the lowest percentage of approval (31 approved, 40 disapproved), which is seen as a reflection of the state of development of the field. Although this is a difficult field in which to teach and practice, the authors feel that the numbers and quality of consultation-liaison programs will grow over the next 10 years and that the proliferation of training programs for primary care physicians and the return of psychiatry to the mainstream of medicine will facilitate this growth.
PMID:842754
Psychiatric education: state of the art, 1976
Am J Psychiatry. 1977 Mar;134 Suppl:suppl 2-6.
ABSTRACT
The authors describe an extraordinary review of 527 programs in 205 institutions conducted by the Psychiatry Education Branch of NIMH. Each institution was evaluated by 2 site visitors, whose findings were reviewed by a group of 12 special consultants. These consultants voted on approval of grant applications and assigned priorities to those which were approved. Direct results of the review included approval of 69% of the programs, increased support of programs in medical student education, consultation-liaison psychiatry, and psychiatric investigation, but a decrease in the total number of institutions supported. Indirect results were the encouragement of self-evaluation in each program reviewed, the valuable exchange of ideas among the educators involved in the review process, and implications for future reviews. The authors, who believe that psychiatric education is in good health, discuss the findings of this review in terms of the future of the field.
PMID:842753
1976
Psychiatry and the primary care physician
JAMA. 1976 Aug 23;236(8):944-5.
ABSTRACT
Psychiatry makes an important contribution to the training and practice of primary care physicians by emphasizing a holistic approach to patient care, by teaching psychiatric skills and by providing knowledge that enables primary care physicians to give basic psychological care to the large numbers of their patients who need it. Consultation-liaison psychiatry and psychiatry education programs for medical students, both of which are given high priority for support by the Psychiatry Education Branch of National Institute of Mental Health (NIMH), are model settings in which to teach the psychiatric aspects of primary care.
PMID:988894
The development of criteria for evaluating psychiatric education programs
Arch Gen Psychiatry. 1976 Apr;33(4):439-42. doi: 10.1001/archpsyc.1976.01770040019005.
ABSTRACT
During the last year, the Psychiatry Education Branch of the National Institute of Mental Health undertook an exhaustive review of 530 training proposals from 205 institutions. The scope of such an endeavor, as well as the desire to maintain peer review, necessitated the recruitment of 90 outside consultants. The need for consistency of judgment among a large group of site visitors gave rise to a document that detailed points of concern in the evaluation of psychiatric training programs. Broader dissemination of this document might be useful in a program's self-evaluation, and might further its understanding of the site-visit process. The result of many such evaluations should be the improvement of psychiatric education throughout the country.
PMID:180928 | DOI:10.1001/archpsyc.1976.01770040019005